In this new project we will explore the role of sensory nerves in bone. In contrast to increasing body of work on to the role of angiogenesis in bone development, few studies have investigated the role of nerves in bone despite a wealth of circumstantial evidence implicating the importance of innervation in skeletal development and repair. This knowledge gap is in part due the difficulty of identifying nerve fibers in calcified tissue and the lack of tractable model systems for study skeletal innervation. To overcome these limitations, our laboratory has validated mouse models for visualizing and disrupting functional signaling of sensory nerves that innervate the skeleton. Using these models we demonstrate that tropomyosin receptor kinase A (TrkA) expressing sensory neurons emanating from the dorsal root ganglion project axons to nerve growth factor (NGF) expressing perichondral cells of developing limbs coincident with incipient mineralization of adjacent cartilage. Elimination of TrkA kinase activity in these sensory nerves during embryogenesis retards axonal ingrowth and attenuates nascent bone mineralization. Disruption of TrkA signaling during embryogenesis reduces postnatal bone acquisition and retards the regeneration of adult bone in response to experimental fracture. These observations, and other studies described below, provide direct evidence for the requirement of TrkA sensory nerves in bone development, acquisition and repair. The studies outlined in this proposal will explore the mechanisms through which sensory nerves function to promote osteogenesis. Our approach will test the hypothesis that nerve growth factor (NGF) produced in the developing and injured limb mesenchyme activates TrkA sensory neurons to promote their survival and guide their axons to primary ossification centers to initiate osteoblast differentiation. This hypothesis will be tested in a setting of bone development (Aim 1) and in response to an established model of experimental bone repair (Aim 2). We believe that our project will yield new insights into the role of sensory nerves in healthy humans and will ultimately inform on the neuropathological manifestations associated with certain bone disorders.